Novel 19-nor-testosterone-17-hemiacetals and -hemiacetal esters



United States Patent 3,264,285 NOVEL 19-NOR-TESTOSTERONE-17-HEMI- ACETALS AND -HEMIACETAL ESTERS Poul Borrevang, Copenhagen, Denmark, assignor to v Lovcns Kemiske Fabrik ved A. Kongsted, Ballerup, Denmark, a firm No Drawing. Filed July 3, 1961, Ser. No. 121,334 Claims priority, application Great Britain, July 13, 1960, 24,462/ 60 13 Claims. (Cl. 260-2395) This invention relates to novel l9-nor-testosterone-17- hemiacetals and -hemi'acetal esters having the general formula:

r is" Ol U in which R is a group selected from the class of unsubstituted aliphatic groups and aliphatic groups substituted by at least one halogen atom, at least one aromatic group, the phenoxy group and at least one heterocyclic group, and R is a member of the class consisting of a hydroxy group and an ester group.

The carbon atom marked by an asterisk in Formula I is an asymmetric carbon atom, from which it appears that there may be the possibility of substances according to the formula existing in two stereoisomerie forms differing by R and R being interchanged.

In the case-0f several substances produced according to the present invention, the existence of the two forms stereoisometric with respect to the carbon atom marked has been realised and is some cases their properties have been found to differ to anot inconsiderable degree. In such cases, when both of the forms which are stereois omeric .in the sense mentioned above are described in the following, they will be designated as the lower melting and the higher melting form. The invention is concerned with the stereoisomers individually as well as with mixtures thereof as far as stereoisornery in this respect concerns; I

In other cases, however, one of the two forms may be produced predominantly and the other form may belost during the processes of purification so thatfor this reason only one form has been located. There may be other reasons, however, why in some particular case but one of the stereoisomeric forms has been located, among which may be mention-ed that in some cases only one form may actually exist, f. inst. owing to steric hindrances in the molecule.

The 19-nor-testosterone-hemiacetals and esters are capable of exerting anabolic and androgenic activities. In clinical therapy, however, it is particularly the anabolic activity which is interesting, and for such therapeutical purposes the said derivatives may f. inst. be administered in the form of injections of a suitable oil, in which the-free hemiacetal or hemiacetal ester has been dissolved or dispersed, or. in the form of injections of aqueous suspensions of the crystalline derivatives. For

-hemiacetal "ice the latter purpose especially the hemiacetal esters are suitable as a therapeutical component, since they are more stable in the presence of water than the free hemiacetals themselves.

According to tests carried out in connection with the present invention it has now been found that when the 17-hydroxy-group of l9-nor-testosterone is converted into a hemiacetal group or a hemiacetal ester group, certain of the derivatives attained, if administered in one of the forms mentioned above, show a more protracted effect than the hitherto known derivatives of l9-nor-testosterone such as its phenylpropionic acid ester or other esters when similarly administered.

Moreover it has been found that the ratio between the anabolic and androgenic activity of the 19 -nor-testosterone may be changed by converting this steroid into the derivatives forming the subject matter of the present invention. This change may be in a desirable direction with regard to particular therapeutical purposes. I

As an illustrating example of the latter effect may be mentioned that the anabolic property of 19-nor-testosterone-chloral-hemiacetal acetate is equal to that of 19- nor-testosterone-phenylpropionate, while the androgenic property of the said hemiacetal ester amounts to only 60% of that of the reference substance. This appears from animal experiments in which the androgenic and anabolic potency of the said substances were evaluated by weighing the vesiculae seminalis+prostata and levator ani, re-

spectively, from groups of dissected castrated male rats which had been treated with a single subcutaneous injection with an oily solution of the steroid compound in question 8 days before killing.

In view of this effect the l9-nor-testosterone-hemiacetal acetate may be u'sed in the treatment of surgical patients in order to shorten the convalescence period.

'On the other hand the protracted effect obtained when administering the lower melting form of 19-nor-testosterone-chloral-hemiacetal-furanate has been ascertained in a biological test in which a number of test animals, castrated male rats, had been divided into three groups and each animal of each group had received an injection of 3 mgs. of 19-nor-testosterone-chloralhemiacetal-fumnate dissolved in oil, 3 mgs. of the same substance in the form of a aqueous suspension of crystals and 3 mgs. of 19-nor-testosterone-phenylpropionate dissolved in oil, respectively.

v10 animals from each group were killed 1, 2, 3, 4 and 8 weeks after injection and the average weight of levator ani collected from the dissected animals of the group was used for measuring the anabolic activity. The re sults obtained are given in the following table, from which the favourable protracted effect of 19-nor-testosterone-chloral-hemiacetal-furanate (lower melting form) will appear. I

The two steroeisomeric forms of the hemiacetals or' hemiacetal esters forming the. subject matter of the present'invention have been found to exert equal biological activity, whereas their potency may differ to a certain. degree.

A further object of the present invention is a method of producing the 19-nor-testosterone derivatives above defined. According to this method 19-nor-testosteroneis reacted with an aliphatic aldehyde which may contain as substituents-one or more-halogen atoms, aromatic groups- '10 including a phenoxy group, or. a heterocyclic group or. with a reactive derivative of they aldehyde, after'whichq one or both of the stereoisometric. formsof :the .hemiacetal obtaineda mixture of the, stereoisomer-is isolated Y and purified or, when esters are desired, the crude hemiacetal obtained by the aforenamed. reaction is'further. reacted with anacylating agent containing the acyl group corresponding to the acid with which the said hemiacetal,

is to be esterified, .after which oneorboth of the stereoiso-- meric forms of thehemiacetal ester is or are isolated .and.

purified or the separated stereosiomeric forms of the free hemiacetal are esterified individually.

The reaction'can be carried out in dilute solution, f.

instaby dissolving the s19-nor-testosterone in a suitable;-

solvent. and adding the aldehyde, or the aldehyde may itself be used as a solvent, after which the mixture 'is left. standing at a suitable temperature forthe period of.

time required to complete the desired reaction. If the.

temperature is about 20 C., the reactionsmay be completed within a few hours or bystanding overnight.

As suitable solvents may be mentioned, by wayof example, benzene, toluene, ether, dioxane, pyridine-or similar solvents.

As is well known aldehydes and alcohols react under. suitable conditions to produce. acetals or hemiacetals in high yield and many aldehydes can be used inthe method E of the present invention. It is further known that by.

reactionwith :water some aldehydes are converted into hydrates, which reaction is analogous to the formation of 1 acetals or hemiacetals so that aldehydes capableof-forming hydrates are usually capable of readily forming: metals or hemiacetals.

Preferred aldehydes used asraw material in [the method I are chloral, bromal, fluor al and other halogenated aliphatic aldehydes I as for. inst. butylchloral (2,2,3-dichloralhydrate is floural hydrate may be substituted for chloral,

bromal or fluoral, respectively.

"Wheniperforming the reaction as described ahereinbe-,

fore the 19-nor-testosterone will usually dissolve in the.- reaction mixture after shaking for a while. .During the.

reaction the hemiacetal may precipitate or it can be pre-. cipitated after conclusion of .the reaction by adding to the :mixture" a component capable of reducing the .solu'-. bility, of the reaction product.

In many reactions, however, only one of the two stereoisomeric forms is produced in high yield, so that the minor amounts of the other form get lost in the reaction 'mixture', from which the crude hemiacetal has been precipitated.

The crude products thus precipitated may be isolated, f. inst. by filtration, and purified by recrystallization from' asuit-ables-olvent or mixture of solvents, the process of Rn'thermore' butanal) and aliphatic aldehydes substituted by aromatic or heterocyclic groups, as f. inst. phenoxy-aldehyde and purification being repeated until the substance obtained In some cases the purification of-the derivatives, or the. process of separation of the two stereoisomeric forms, is facilitated by esterification of the free hydroxy groups containedin the. hemiacetal group before recrystallization, :the esters; crystallizing in many cases'more readily than the corresponding free hemiacetals.

Some esters possess properties. :useful for particular therapeuticalipurposes, .the utilization ;of the physiological activity of thesteroid compound depending in many; cases. on the form of administration ;used.l

Thus by esterification of the free hydroxy group of-the hemiacetal group' slightly water; soluble esters can be formed, which have particularly F favourable properties with regardxto protracted effect, as mentioned in the: foregoing. By esterification of the free hydroxy group .of the hemiacetal group with f. inst. amino-acids" or, one of the carboxyl groups of succinic' acid, esters are produced the salts of which with acids or bases, respectively, are readily soluble in water.

esters of the inventionare, f. inst, .the formyh, acetyl 1 propionyL, butyryl isobutyryl cyclopentyl-propionyl phenylpropionyl, enanthyl-, furoyl-, glycyl succiny-l., and glutaryl groups.

The invention willnow be illustrated by the following examples.

Example 1. -1-9rn0r-test0sterone-1 Z-chloral-hemiacetal (higher melting form) 2.7 g.; of -l9.-nor-testosteronewwere addedtoa. solution of 1.7 g. of anhydrous chloral in 10 ml. of dry benzene. After a couple .of minutes: a clear solution was obtained, and after about .10 minutes the solution solidified completely. After. standing :for about further 10 minutes, the solid substance was filtered ioff: and .washed. with a little benzene andv petrolether. After .dryingat room temperature, 3.6g. of the desired'substance. ,were ob-' tained; By recrystallization from ethyl acetate the mo stance had a melting point of :184-186. ,The ultraviolet "spectrum showed .amaximumiof 240 m (in ethanol) e=.1.7,400.'

Calculated: C, 56.95; H, 6.45; Cl, 25.22. Found: C, 57.19; H, 6.52; Cl, 25.22.

Example 2.'19-nor-testosterone-1lechloral-hemiacetal (higher melting form) 6.5 g. of 19-nor-testosterone were .dissolved in 26 ml.

of anhydrous'chloral, and the'mixture was shaken. After .two'minutes asubstance beganztoprecipitate, and after shakingfor further 15 minutes the substance thus precipitated .was isolatedbyfiltration. The filteracake was washed with benzene; and thereafter dried. The product thus obtained was identical with that prepared in Example. 1.

Example 3.-19-n0r-test0sterone-17-chl0ral-hemiacetal acetate (higher melting form) 2.0 g. of 19-nor-testosterone-17-chloral-hemiacetalV were dissolved in a mixture of 6 ml. of dry pyridine and 6 ml. of acetic anhydride. After standing for 17 hours at room temperature, the solution ;was evaporated in vacuo on a steam-bath to a syrupyconsistency. The residue wasdissolved by heating in 96% ethanol, and after. standing in' antice-box the crystals precipitated were fil tered off, washed with a little of 96% ethanol and dried at room temperature- Thereby 1.1 g. of the desiredsubstance was obtained. By recrystallization from 96% ethanol the substance had a melting-point of -151. The ultra-violet spectrum showed 'a maximum .at 239 m (in ethanol), e=17,400.

Calculated: C, 56.97; H, 6.30; C], 22.93; Found? C, 56.96; H, 6.56; Cl,22.68.

By substituting propionic anhydride for acetic anhydride, the '19-nor-testosterone-17-chloral-hemiacetal propionate was prepared following the. method described The acid groups preferred-as constituents of hemiacetal above, the propionate obtained having a melting-point of 102104 and a maximum at 239 III/.L in the ultraviolet spectrum (e=16,800). It is not known whether this compound is the higher melting or the lower melting stereoisomer. 1

Example 4.-19-n0r-testosterone-chloral-hemiacetal isobutynate 6.3 g. of 19-nor-testosterone-chloral-hemiacetal prepared as described in Example 1 were dissolved in 15 ml. of pyridine. The solution was cooled to a temperature of -20 C., after which, in a nitrogen atmosphere, 3 g. of isobutyric acid chloride were added dropwise. The reaction mixture was stirred for 15 minutes at 20 C. and thereafter placed in a refrigerator having a temperature of +2 C., in which it was left standing for 2 days.

Then to-the reaction mixture was added a mixture of 100 ml. of ether and 100 ml. of ethyl acetate, and the organic phase was extracted twice with 50 ml. of 2 N sulphuric acid, once with water, twice with 50 ml. of 2 N sodium hydroxide and finally with water. After drying the organic phase over Na SO it was evaporated in vacuo to dryness, and the oily residue was recrystallized from 80% methanol. The crystalline substance contained one mole of crystal methanol and had a melting point of 85-87. The ultra-violet spectrum showed a maximum at 239 m (-e=l6,900).

Calculated: C, 57.31; H, 7.12; CI, 20.30. Found: C, 57.39; H, 7.03; Cl, 21.19.

Example 5.19-n0r-testosterone-chloral-hemiacetal furanate (lower melting form) Following the procedure described in Example 4, but substituting furoyl chloride for isobutyric acid chloride, a furanate was obtained having a melting point of 121 122 C. after recrystallization from 96% ethanol. The ultra-violet spectrum showed a maximum at 246 my. (5:26800).

Calculated: C, 58.20; H, 5.67; Cl, 20.62. Found: C, 57.98; H, 5.71; Cl, 20.54.

Example 6.-19-nt0r-test0ster0ne-chloral-hem iacetal formate 3 g. of 19-nor-testosterone-chloral-hemiacetal prepared as described in Example 1 were dissolved in 15 ml. of pyridine, after which a mixture of 7.5 ml. of acetic anhydride and 2.9 ml. of formic acid which had before been left standing for 24 hours was added. The reaction mixture was left standing for 4 /2 hours and thereafter evaporated to dryness. The residue was recrystallized from ether and the substance thus obtained was further recrystallized from 96% ethanol. The desired substance thus obtained from 96% ethanol, had a melting point of 196- 197, and the ultra-violet spectrum showed a maximum at 239 mu (s=l7,300).

Calculated: C, 56.07; H, 6.05; Cl, 23.65. Found: C, 56.04; H, 6.18; Cl, 23.61.

Example 7.19-n0r-test0ster0ne-17-phen0xyacetalaldehyde-hemiacetal 2.7 g. of 19-nor-testosterone were added to a solution of 1.6 g. of phenoxyacetaldehyde in ml. of dry benzene, whereby a clear solution immediately was formed. After standing for 3 hours at room temperature, a little of ether was added and the solution was poured into petrolether. Thereby an oily substance separated. After standing for a while, the supernatant phase was decanted from the oily substance, which crystallized by addition of a small quantity of ether. The crystals were filtered off, washed with a little of petrolether, and after drying in the air at room temperature, 0.5 g. of the desired substance was obtained having a melting point of 124-127 The ultra-violet spectrum showed maxima at 224 m and 240 m (in ethanol), (e=16,100) and (e=18,300).

Calculated: C, 76.06; H, 8.35. Found: C, 76.11; H, 839.

Following the procedure described in Example 6 for the preparation of 19-nor-testosterone-chloral-hemiacetal formate, but substituting 19-nor-testosterone-phenoxyacetaldehyde-hemiacetal for 19-nor-testosterone-chloralhemiacetal, the formate was produced with a melting point of 173-175 C.

Calculated: C, 73.94; H, 7.82. Found: C, 73.91; H, 7.96.

Example 8 .1 9-n0r-testoster0ne-1 7-(pyridine- 4 -aldehyde -hemiacetal 2.0 g. of 19-nor-testosterone were dissolved at about 50 C. in 3.5 ml. of py1idine-4-aldehyde. After standing overnight, the crystals precipitated were filtered oil and washed with a little ether. After drying in the air at room temperature, 1.1 g. of the desired substance was obtained. By recrystallization from acetone the substance had a melting-point of 135-138". The ultra-violet spectrum showed a maximum at 240 m (in ethanol) (e=l9,000).

Calculated: C, 75.56; H, 8.19; N, 3.67. Found: C, 75.55; H, 8.27; N, 3.68.

Example 9.-1 9-n0r-testoster0ne-17-butylchloralhemiacetal 2.7 g. of 19-nor-testosterone were added to a solution of 2.0 g. of butyl chloral (a,oz,fl-tl'iChlOIOblltYlfildlWdG) in 10 ml. of dry benzene, whereby a clear solution immediately was obtained. After standing for 2% hours at room temperature, 30 ml. of ether were added, and the solution was poured into petrolether. After standing for a while the substance crystallized, was filtered off and washed with a small quantity of petrolether. After drying in the air at room temperature, 1.6 g. of the desired substance were obtained. By recrystallization from ethyl acetate, a melting-point of 154-156 was obtained. The ultra-violet spectrum showed a maximum at 240 m (in ethanol) e=17,400.

Calculated: C, 58.74; H, 6.96; Cl, 23.64. Found: C, 58.56; H, 7.09; Cl, 23.71.

Following the procedure described in Example 3, l9- nor-testosterone-butylchloral-hemiacetal acetate was prepared having a melting point of 133-134 and a maximum in the ultra-violet spectrum at 240 m (e: 17,200).

Calculated: C, 58.60; H, 6.76; Cl, 21.63. Found: C, 58.69; H, 6.88; Cl, 21.48.

Example 10.--19-n0r-testosterone-chloral-hemiacetal (lower melting form) 6.5 g. of 19-nor-testosterone were dissolved in 10 ml. of pyridine, after which 10 ml. of anhydrous chloral were added. The reaction mixture was stirred for an hour, ml. of water were added and the stirring was continued for further half-an-hour. The water-phase Was decanted from the oily substance which had precipitated, and the latter substance was recrystallized from 15 ml. of acetone. The crystals obtained were filtered 01f and the filteracake washed with a mixture of acetone and petrolether (1:1) and dried. The desired compound obtained had a melting point of 169-172" and is an isomer of that prepared in Example 1.

Example 11.-19-n0r-testosterone-chloral-hemiacetal acetate (lower melting form) The substance prepared in Example 10 was esterified following the procedure described in Example 3, whereby the desired substance was obtained which after recrystallization from ethyl acetate had a M.P. of 132- and a maximum in the ultra-violet spectrum at 240 mp. (e=16,600). [oc ]=+27.3 in CHC1 Calculated: C, 56.96; H, 6.30; Cl 22.95. Found: C, 56.88; H, 6.46; CI, 22.78. This compound is an isomer of that described in Example 3.

Example 12 .-19-n0r-lest0ster0ne-chloral-hemiacetal fm'anate (higher melting form) The substance prepared asdescribed in Example 10 was esterified as described in Example 5, "thereby yielding the; desired furanate having a melting-point of 2294 By evaporation ,of the mother-liquors obtained in. the said Example to dryness and recrystallization of the.

residue from'ether, the higher melting form. of the .19.-v

nor-testosterone-chloral-hemiacetal.rturanate may also be obtained having a melting-point of 221226, which after recrystallization of the substance from 99% ethanol rose 1 Example I3.19-nor-testoster0ne-bromal-hemiacetal In nitrogematrnosphere, 2.7 g. of 19-nor-testosterone were mixed'with 5 mLof dry benzene and 3.2 g. of bromal. The steroid compound dissolved immediately,

but after 5 minutes the reaction mixture became partlyi. solid owing to the precipitation of the hemiacetal.v The substance precipitated was filtered ofi and the filter-cake washed with a little amount of ether. After drying and recrystallization of the substance from acetone, the vdesired hemiacetal was obtained with a melting-point of 90-.92".

Calculated: C,"43.26;.H, 4.90; Br, 43.19. Found: C,

43.03; H, 5.08; Br, 42.91.

What is claimed is: 1. A compound selected from the group consisting of v19nor-testosterone-17-bromal hemiacetal and esters thereof with an acid group selected from the group com I sisting of sformyl, acetyl, propionyl, butyryl, isobutyryl, cyclopentylpropionyl; phenyl propionyl, enanthyl,1furoylglycyl, suocinyl, and glutaryl groups.

2. A compound selectedfrorn the group consisting.

of 19 nor testosterone 17 phenoxyacetaldehydehemiacetal and esters thereof with an acid group selected tfrom=the group consisting of formyl,.acetyl, propionyl,

butyryl, isobutyryl, cyclopentyl-propionyl, phenyl propionyl, enanthyl, furoyl-, glycyl, succinyl, and glutaryl groups.

3. 19 nor-testosterone-17-phenoxyacetaldehyde-hemiacetal formate.

4. A compound selected from the group consisting of I 19-nor-testosterone-17-butylchloral-hemiacetal and. esters thereof with an acid group selected fromthe group consisting of formyl, acetyl, propionyl, butyryl, isobutyryl, cyclopentyl-propionyl, phenyl propionyl, enanthyl, furoyl-,' glycyl, succinyl, and glutaryl groups. p

5. 19 nor-estosterone-17-butylchloral-hemiacetal acetate.

6. A compound selected from the group consisting of 19 nor-testosterone-17-(pyridine-4 aldehyde -hemiacetal and vestersthereof with an acid group selected from the group consisting of formyl, acetyl, propionyl, butyryl, isobutyryl, cyclopentyl-propiony-l, phenyl propionyl, enan-' thyl, furoyl-, glycyl, succinyl, and glutaryl groups.

7. .The high melting stereoisomeric form of 19-nortestosterone-17-chloral-hemiacetal furanate of M.P. 229 233 C.

8. The low melting stereoisomeric form of 19-nortestosterone-17-chloral-herniacetal furanate of MP. *121- 122". C;

9. A method of producing the novel 18-nor-testoster- Q one-l7-herniacetals and -herniacetal esterswith an acid group selected from the group consisting of formyl, acetyl, propionyl, buty ryl, isobutyryl, cyclopentyl-propi ostereoisomeric forms of the hemiacetal are=obtained,'

in :Which R? is analiphatioradical containing not more than 3 carbonatomswhi'ch. is substituted with members of the class consisting ofhaloge ns and aromatic groups and phenoxygroups, and R t isa member of the class. consisting of a hydroxy group and ester groups, .the asterisk in the formula indicatingt hat the: carbon atom of thehemiacetalgroup thus markedis an asymmerically substitued carbon atom, according to whichthe 19-nor.-. testosterone. is reacted with an aliphatic aldehyde selected from the group' consisting of aldehydes having not more than four carbon atoms and said aldehydes having as. sub-. stituents members of .the class consisting of halogens, aromatic groups, includingphenoxy groups, a hydroxy groupand esterv groups, with an acid .groupselected from the group consisting of, formyl, acetyl, propionyl, fbutyryl, isobutyryl, cyclopentyl-propionyl, phenyl propionyl, enanthyl, furoyl-, glycyl, succinyl,1and glutaryl groups Where. after the hemiacetal formed is recovered.

10. A-method; according to claim==9, in which the aldehyde used 'isaddedi in the form of a reactivederivw: tive of the said aldehyde.

lLiA'method according to 1 claim 9, in which two in which R ispyridine, and R is a member of the class" consisting. .of a hydroxy group and ester groups, the asterisk in the formulav indicating that the carbon atom of the hemiacetal group thus;marked is an asymmetrically substituted carbon. atom. 1. i

ReferencesCited Eby the Examiner UNITED STATES'PATENTS 2,933,514 4/1960 Borrevang ,26,0.397.4 OTHER IREFERENCES Fieser and Fieser, Steroids, (1959), Reinhold Publish ing Corp, New York, N'.Y., pp. 692-'698.

LEWIS GOTTS,'Primary Examiner. MORRIS LIEBMAN, IRVING MARCUS, Examiners.

.HENRY A. FRENCH, Assistant Examiner. 

13. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF NOVEL 19-NOR-TESTOSTERONE-17-HEMIACETALS AND HEMIACETAL ESTERS WITH AN ACID GROUPS SELECTED FROM THE GROUP CONSISTING OF FORMYL, ACETYL, PROPINYL, BUTYRYL, ISOBUTYRYL, CYCLOPENTYL-PROPIONYL, PHENYL PROPIONYL, ENANTHYL, FUROYL-, GLYCYL, SUCCINYL, AND GLUTARYL GROUPS, HAVING THE GENERAL STRUCTURAL FORMULA 